Osmotic devices have demonstrated utility in delivering useful active agents such as medicines, nutrients, food products, pesticides, herbicides, germicides, algaecides, chemical reagents, and others known to those of ordinary skill to an environment of use in a controlled manner over prolonged periods of time. Known devices include tablets, pastilles, pills or capsules and others that use osmotic pressure to control the release of the active agent contained in the core of the osmotic device. Some osmotic devices may also include layers comprising one or more materials that are subject to erosion or that slowly dissolve in the environment of use thereby gradually dispensing the active agent.
Osmotic salts that exhibit an osmotic pressure gradient against an external fluid across the semipermeable wall of the osmotic devices have been used in the core of the osmotic devices for long time. U.S. Pat. No. 3,977,404, U.S. Pat. No. 4,008,719, U.S. Pat. No. 4,014,334, U.S. Pat. No. 4,034,758, and U.S. Pat. No. 4,077,407 to Theeuwes et al., U.S. Pat. No. 4,036,227 and U.S. Pat. No. 4,093,708 to Zaffaroni et al., describe that the osmotic salts are used mixed with an agent that has limited solubility in the external fluid with the osmotic salt forming a saturated solution containing agent that is osmotically delivered from the device. The osmotic salts are used by homogenously or heterogeneously mixing the osmotic salt or a mixture of them with an active agent, either before they are charged into the reservoir, or by self-mixing after they are charged into the reservoir. In operation, the osmotic salt attract fluid into the device producing a solution of the osmotic salt which is delivered from the device concomitantly transporting undissolved and dissolved agent to the exterior of the device. U.S. Pat. No. 6,248,359 and U.S. Pat. No. 6,599,532 to Faour, and U.S. Pat. No. 6,569,456, U.S. Pat. No. 6,572,890, U.S. Pat. No. 6,599,284, U.S. Pat. No. 6,599,532, U.S. Pat. No. 6,605,302, and U.S. Pat. No. 6,613,357 to Faour et al., and U.S. Pat. No. 6,521,255 to Vergez et al., teaches the osmotic salts will aid in either the suspension or dissolution of the active drug in the core. The osmotic salts can be incorporated to the core of the osmotic device to control the release of the active drug therefrom. All above referenced Patents do not disclose that the release rate of the active drug is reduced and the release profile of the active drug is modified by increasing the amount of the osmotic salt in the core.
The controlled release of active agents from an osmotic device can occur according to many different release profiles: first order, pseudo-first order, zero order, pseudo-zero order, sigmoidal, delayed, constant rate of release, pulsatile and some combinations thereof. Typically, a drug must have a solubility within the range of 50-300 mg/ml in order to be delivered effectively by an osmotic device.
It is generally well known that highly soluble drug salts can be difficult to formulate into osmotic devices. The more soluble they are, generally the more difficult they are to formulate into osmotic devices. This is because the drug salts tend to dissolve too quickly thereby leading to premature release of the drug, load dumping of the drug or rapid rather than controlled release of the drug. According to McClelland et al. (Pharm. Res. (1991), 8(1), 88-92), drugs with a water solubility of ≦50 mg/ml should be released by an osmotic device in a controlled manner such that ≧95% of the drug load is released according to zero-order kinetics. Drugs with a high water solubility (e.g., ≧300 mg/ml) should be released by an osmotic device in a controlled manner such that only a very small percentage of the drug load is released according to zero-order kinetics. McClelland et al. therefore propose modulation of the drug solubility in an attempt to change the release profile of a drug from first order to zero order. In a particular embodiment, McClelland et al. demonstrate modulation of the solubility of diltiazem with sodium chloride in an osmotic device.
Due to the complexity of interactions occurring within the core of an osmotic device, no generally applicable approach has been developed to control and reduce the rate of dissolution of very water soluble drugs.
The use of sodium chloride as an osmagent in an osmotic device is widely known. The art generally teaches that increasing the amount of osmagent results in an increase of osmotic pressure and thereby an increase in the rate of release of drug from the core of the osmotic device. The prior art discloses osmotic devices having a bi-layered or multi-layered core, wherein at least one of the layers is a “push” or “displacement” layer comprising sodium chloride in combination with an osmopolymer or a water swellable polymer. The NaCl serves to draw water within the polymer matrix thereby wetting and swelling the polymer.
An osmotic device having a unitary core comprising a pharmaceutically acceptable salt of a drug in combination with sodium chloride and other excipients is known. In particular, the art discloses osmotic devices having a unitary core comprising drugs such as pseudoephedrine hydrochloride (Johnson et al. in U.S. Pat. No. 6,537,573; Faour et al. in U.S. Pat. No. 6,004,582; Hamel et al. in U.S. Pat. No. 4,801,461; Chen et al. in U.S. Pat. No. 5,458,887, U.S. Pat. No. 5,654,005, and U.S. Pat. No. 5,558,879), venlafaxine hydrochloride (Faour et al. in U.S. Pat. No. 6,352,721), reboxetine methane sulfonate (Seroff et al. in U.S. Pat. No. 6,387,403), carbamazepine (Puthli et al. in U.S. Pat. No. 6,534,090), rofecoxib (Faour et al. in U.S. Pat. No. 6,491,949), cisapride monohydrate (Faour et al. in U.S. Pat. No. 6,004,582), nifedipine (Kettelhoit et al. in U.S. Pat. No. 6,294,201); or other drugs (Chen et al. in U.S. Pat. No. 5,736,159 and U.S. Pat. No. 5,837,379) in combination with sodium chloride and other excipients. The art also discloses osmotic devices having bi-layered or multi-layered cores, wherein one of the layers includes a drug and sodium chloride among other excipients (Wong et al. in U.S. Pat. No. 5,785,994; Kuczynski et al. in U.S. Pat. No. 5,866,164). Osmotic devices having a bi-layered core comprising an active drug and sodium chloride in the drug-containing layer are disclosed in U.S. Pat. No. 6,352,721 to Faour, which teaches about three osmotic devices containing a core layer comprising venlafaxine hydrochloride and sodium chloride, cisapride and sodium chloride, and nifedipine and sodium chloride, respectively, U.S. Pat. No. 5,674,895, U.S. Pat. No. 5,840,754, U.S. Pat. No. 5,912,268, U.S. Pat. No. 6,124,355, U.S. Pat. No. 6,262,115 and U.S. patent application Ser. No. 20010005728, to Guittard et al., and U.S. patent application Ser. No. 20010009995 to Gupta et al., which disclose a core layer comprising oxybutynin and sodium chloride, and U.S. Pat. No. 6,387,403 to Seroff et al., which discloses a core layer comprising reboxetine methane sulfonate and sodium chloride. International documents WO03/039519 and WO03/039436 to Vergez et al., teach about osmotic devices comprising bi-layered cores comprising a drug in each layer of the core; drug-layer compositions comprising sodium chloride are exemplified, wherein the sodium chloride is among the osmagents that will aid in either the suspension or dissolution of the active drugs of the core. Osmotic devices having a multi-layered core are disclosed in U.S. Pat. No. 5,785,994 to Wong et al., wherein one of the layers includes a drug, such as diltiazem HCl, and potassium chloride among other excipients. In all above-referenced Patents, the osmotic salt is disclosed as an osmagent that increases the osmotic pressure of the core by attracting fluid into the device, and thereby producing a solution or suspension of the active drug that is then delivered from the device at increased rate. None of above-referenced Patents disclose that the release rate of the active drug is reduced and that the release profile of the active drug is modified by increasing the amount of the osmotic salt in the core. The weight percentages of sodium chloride and the drug as disclosed in the prior art are highly variable.
However, the art is not consistent regarding use of NaCl in osmotic devices. Ramakrishna et al. (Pharmazie (2001), 56(12), 958-962) disclose that increasing the amount of NaCl present in the core of an osmotic device is primarily responsible for decreasing the rate of release, delaying the initial release and affecting a zero order release of naproxen sodium.
McClelland et al. (1991) disclose that release of diltiazem hydrochloride from an osmotic device is slowed down by increasing the amount of NaCl added to the core of the osmotic device. They also report that the release profile can be changed from a first order release profile to a second order release profile. However, of particular interest, McClelland et al. specifically state that the NaCl must be present in controlled release form as NaCl crystals coated with cellulose acetate butyrate to form mini osmotic pumps. They state, “This pump-in-a-pump design was necessary to prevent the rapid depletion, and large attendant concentration variation, of the solubility modulating agent (sodium chloride) within the diltiazem hydrochloride core tablet environment.” Accordingly, McClelland et al. teach that the desired effect provided by sodium chloride cannot be achieved with uncoated sodium chloride crystals.
The prior art also discloses the use of sodium chloride to reduce the rate of release or reduce the lag time in release of a drug salt from a coated controlled release device. Lin et al. (J. Pharm. Sci. (2002), 91(9), 2040-2046) disclose that increasing the amount of NaCl present in the core of a compression-coated ethylcellulose tablet reduces the lag time to initial drug release.
Accordingly, the art in this area is unpredictable, meaning that one cannot predict with certainty, or a priori, whether increasing the amount of sodium chloride in an osmotic pump containing a drug salt will decrease or increase the rate of release of the drug salt. This is particularly true for specific drug salt and osmotic salt combinations.
Venlafaxine, have been tested for the treatment of depression and symptoms of anxiety. EFFEXOR XR™ (venlafaxine hydrochloride) is commercially available in an extended release capsule dosage form from Wyeth Ayerst in 37.5, 75, and 150 mg strengths. The capsule is disclosed in U.S. Pat. No. 4,535,186. EFFEXOR XR™ is indicated for the treatment of depression and generalized anxiety disorder. Clinical depression is a disorder characterized by low self-esteem, guilt, self-reproach, introversion, sadness, despair, sleeping disorders, eating disorders or discouragement. Depression generally causes a lower or decrease of a person's function. Anxiety is a disorder characterized by responses to anticipation of unreal or imagined danger. It manifests itself as increased heart rate, altered respiration rate, sweating, trembling, weakness, or fatigue. Major depression and anxiety occur concomitantly in more patients than either one alone. When these disorders occur together, they are associated with more severe symptoms, increased impairment of function, a longer chronic course, poorer outcome, and a higher incidence of suicide.
U.S. Pat. No. 6,572,890 to Faour et al. discloses an osmotic device containing controlled release venlafaxine in the core in combination with an anti-psychotic agent in a rapid release external coat. The exemplified single core compositions contain venlafaxine but do not contain sodium chloride. The osmagents used in the core aid in either the suspension or dissolution of the VFX in the core, and can also be incorporated to the core of the osmotic device to control the release of VFX there from. Sodium chloride is not used to reduce the release rate and modify the release profile of the venlafaxine.
It is known in the field of osmotic devices that changing the release profile of a drug can have an effect upon the clinical benefit observed in a patient to which the osmotic device is administered. Depending upon the drug being administered, the disease or disorder being treated, the observed clinical response in a subject and other considerations, a particular controlled release profile will be preferred in providing an intended clinical benefit. In some situations, a zero order release profile is preferred while in others a first order release profile or a sigmoid release profile is observed.
Osmotic devices manufacture with two or more layers in order to provide a desired release rate profile can be difficult to produce and require specialized manufacturing machinery. Therefore, it would be an improvement in the art to provide a controlled release dosage form that is easily manufactured and produces a desired release rate or release rate profile for a desired soluble or insoluble hydrochloride salt of an active agent by modifying the amount of sodium chloride in the core of the osmotic device.